This proposal tests the hypothesis that both irregular and periodic breathing can result from interactions between stochastic disturbances to respiration (i.e., disturbances that are random relative to the respiratory cycle) and the nonlinear deterministic properties of respiratory neurochemical and neuromechanical feedback systems. Such disturbances may originate within the respiratory system (e.g., in receptor or neuronal discharges, in blood gas fluctuations) or external to it (e.g., from higher brain activities). Preliminary experimental and mathematical modelling studies demonstrate that under various normal and pathological conditions "noisy" breath to breath disturbances to respiratory pattern, ventilation, or blood gases can excite additional modes of respiratory behavior, including self-sustaining breath to breath variations in respiratory cycle parameters, irregular apneas, and periodic oscillations in ventilation. Proposed studies will examine first the effects of chemical drive and sleep state on the characteristics of spontaneous disturbances to, and the resulting breath to breath variations in, ventilatory parameters and respiratory EMGs in human subjects. The influence of these disturbances on the occurrence of periodic breathing and apneas will be predicted through mathematical simulations and tested experimentally. Coordinated studies involving awake and asleep humans and anesthetized rats will assess the roles of several physiological mechanisms, including central and peripheral chemoreceptors and pulmonary mechanoreceptors, in promoting oscillations and self-sustaining variations in tidal volume, breath timing, and ventilation. Contributions of these mechanisms will be assessed by first reducing, then enhancing, the physiological activity of each mechanism. These studies will utilize new techniques for optimal control of blood gases in humans and for white-noise identification of feedback system properties. Applicability of the findings to patient populations will be explored using mathematical simulations. These studies will evaluate a new framework for understanding the causes of irregular and periodic breathing, which may be important for developing early therapeutic interventions in patients, and will develop new sensitive techniques for assessing ventilatory stability.